Abstract The proposed project is a pilot clinical trial investigating a potential treatment for hippocampal sclerosis of aging (HS-Aging). A major subtype of ?Alzheimer's disease and related dementia? (ADRD), HS-Aging affects 10-25% of all elderly individuals. HS-Aging is typically misdiagnosed as Probable AD or AD-type dementia in the clinical setting. Unfortunately, there currently is no validated biomarker to diagnose HS-Aging during life, and there is no known therapy. We will test the safety and efficacy of nicorandil for HS-Aging, based on our prior work elucidating a pharmacologically targetable mechanism underlying the disease. Nicorandil is a vasorelaxant drug, used clinically to treat chronic heart failure in the elderly population. Pharmacologically, Nicorandil is an agonist for a protein (SUR2) that is encoded by a gene that we found to be linked to HS-Aging risk. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-Aging pathology in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind, randomized, placebo-controlled, clinical trial of nicorandil in 62 participants (both sexes, >75 years old, CDR 0.5 or 1, with HS-Aging profile in CSF and MRI biomarkers [amyloid and phospho-tau negative, with evidence for hippocampal atrophy; A-/T-/N+]) over a 96-week treatment period; b. Evaluating the safety of nicorandil administration in the elderly at risk for HS-aging (this is the primary outcome measure) that will inform future trial design; and, c. Measuring structural MRI (3D-T1; hippocampal atrophy is the main efficacy outcome measure), cognitive tests, and CSF levels of nicorandil, tau, phospho-tau, and A?(1-42) at baseline and week 96. Specific Aim #2: Optimize and further explore HS-Aging biomarkers by: a. Refining MR imaging analysis (including hippocampal volumetric assays, arterial spin labeling (ASL), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) techniques that may distinguish participants with probable HS-Aging from those with positive AD biomarkers; b. Performing proteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers to complement the A/T/N framework utilizing our prospective cohort with A?(1-42), phospho-tau, and neurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directly test and enhance the clinical utility of the A/T/N framework for diagnosis of degenerative disease state; and, c. Following our published and replicated neurocognitive testing marker that is associated with HS-Aging pathology, we will optimize the clinical and neurocognitive criteria for disease diagnosis based on the prospects of a relatively long-running (96 week) early-phase clinical trial.